Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study.
Goshua George,Pine Alexander B,Meizlish Matthew L,Chang C-Hong,Zhang Hanming,Bahel Parveen,Baluha Audrey,Bar Noffar,Bona Robert D,Burns Adrienne J,Dela Cruz Charles S,Dumont Anne,Halene Stephanie,Hwa John,Koff Jonathan,Menninger Hope,Neparidze Natalia,Price Christina,Siner Jonathan M,Tormey Christopher,Rinder Henry M,Chun Hyung J,Lee Alfred I
The Lancet. Haematology
BACKGROUND:An important feature of severe acute respiratory syndrome coronavirus 2 pathogenesis is COVID-19-associated coagulopathy, characterised by increased thrombotic and microvascular complications. Previous studies have suggested a role for endothelial cell injury in COVID-19-associated coagulopathy. To determine whether endotheliopathy is involved in COVID-19-associated coagulopathy pathogenesis, we assessed markers of endothelial cell and platelet activation in critically and non-critically ill patients admitted to the hospital with COVID-19. METHODS:In this single-centre cross-sectional study, hospitalised adult (≥18 years) patients with laboratory-confirmed COVID-19 were identified in the medical intensive care unit (ICU) or a specialised non-ICU COVID-19 floor in our hospital. Asymptomatic, non-hospitalised controls were recruited as a comparator group for biomarkers that did not have a reference range. We assessed markers of endothelial cell and platelet activation, including von Willebrand Factor (VWF) antigen, soluble thrombomodulin, soluble P-selectin, and soluble CD40 ligand, as well as coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes. We compared the level of each marker in ICU patients, non-ICU patients, and controls, where applicable. We assessed correlations between these laboratory results with clinical outcomes, including hospital discharge and mortality. Kaplan-Meier analysis was used to further explore the association between biochemical markers and survival. FINDINGS:68 patients with COVID-19 were included in the study from April 13 to April 24, 2020, including 48 ICU and 20 non-ICU patients, as well as 13 non-hospitalised, asymptomatic controls. Markers of endothelial cell and platelet activation were significantly elevated in ICU patients compared with non-ICU patients, including VWF antigen (mean 565% [SD 199] in ICU patients vs 278% [133] in non-ICU patients; p<0·0001) and soluble P-selectin (15·9 ng/mL [4·8] vs 11·2 ng/mL [3·1]; p=0·0014). VWF antigen concentrations were also elevated above the normal range in 16 (80%) of 20 non-ICU patients. We found mortality to be significantly correlated with VWF antigen (r = 0·38; p=0·0022) and soluble thrombomodulin (r = 0·38; p=0·0078) among all patients. In all patients, soluble thrombomodulin concentrations greater than 3·26 ng/mL were associated with lower rates of hospital discharge (22 [88%] of 25 patients with low concentrations vs 13 [52%] of 25 patients with high concentrations; p=0·0050) and lower likelihood of survival on Kaplan-Meier analysis (hazard ratio 5·9, 95% CI 1·9-18·4; p=0·0087). INTERPRETATION:Our findings show that endotheliopathy is present in COVID-19 and is likely to be associated with critical illness and death. Early identification of endotheliopathy and strategies to mitigate its progression might improve outcomes in COVID-19. FUNDING:This work was supported by a gift donation from Jack Levin to the Benign Hematology programme at Yale, and the National Institutes of Health.
10.1016/S2352-3026(20)30216-7
COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis.
Chua Robert Lorenz,Lukassen Soeren,Trump Saskia,Hennig Bianca P,Wendisch Daniel,Pott Fabian,Debnath Olivia,Thürmann Loreen,Kurth Florian,Völker Maria Theresa,Kazmierski Julia,Timmermann Bernd,Twardziok Sven,Schneider Stefan,Machleidt Felix,Müller-Redetzky Holger,Maier Melanie,Krannich Alexander,Schmidt Sein,Balzer Felix,Liebig Johannes,Loske Jennifer,Suttorp Norbert,Eils Jürgen,Ishaque Naveed,Liebert Uwe Gerd,von Kalle Christof,Hocke Andreas,Witzenrath Martin,Goffinet Christine,Drosten Christian,Laudi Sven,Lehmann Irina,Conrad Christian,Sander Leif-Erik,Eils Roland
Nature biotechnology
To investigate the immune response and mechanisms associated with severe coronavirus disease 2019 (COVID-19), we performed single-cell RNA sequencing on nasopharyngeal and bronchial samples from 19 clinically well-characterized patients with moderate or critical disease and from five healthy controls. We identified airway epithelial cell types and states vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In patients with COVID-19, epithelial cells showed an average three-fold increase in expression of the SARS-CoV-2 entry receptor ACE2, which correlated with interferon signals by immune cells. Compared to moderate cases, critical cases exhibited stronger interactions between epithelial and immune cells, as indicated by ligand-receptor expression profiles, and activated immune cells, including inflammatory macrophages expressing CCL2, CCL3, CCL20, CXCL1, CXCL3, CXCL10, IL8, IL1B and TNF. The transcriptional differences in critical cases compared to moderate cases likely contribute to clinical observations of heightened inflammatory tissue damage, lung injury and respiratory failure. Our data suggest that pharmacologic inhibition of the CCR1 and/or CCR5 pathways might suppress immune hyperactivation in critical COVID-19.
10.1038/s41587-020-0602-4
The Contribution of the Age Distribution of Cases to COVID-19 Case Fatality Across Countries : A Nine-Country Demographic Study.
Annals of internal medicine
BACKGROUND:There is wide variation in coronavirus disease 2019 (COVID-19) case-fatality rates (CFRs) across countries, leading to uncertainty about the true lethality of the disease. A large part of this variation may be due to the ages of individuals who are tested and identified. OBJECTIVE:To measure the contribution of distortions from the age distributions of confirmed cases to CFRs within and across populations. DESIGN:Cross-sectional demographic study using aggregate data on COVID-19 cases and deaths by age. SETTING:Population-based data from China, France, Germany, Italy, the Netherlands, South Korea, Spain, Switzerland, and the United States. PARTICIPANTS:All individuals with confirmed COVID-19, as reported by each country as of 19 April 2020 ( = 1 223 261). MEASUREMENTS:Age-specific COVID-19 CFRs and age-specific population shares by country. RESULTS:The overall observed CFR varies widely, with the highest rates in Italy (9.3%) and the Netherlands (7.4%) and the lowest rates in South Korea (1.6%) and Germany (0.7%). Adjustment for the age distribution of cases explains 66% of the variation across countries, with a resulting age-standardized median CFR of 1.9%. Among a larger sample of 95 countries, the observed variation in COVID-19 CFRs is 13 times larger than what would be expected on the basis of just differences in the age composition of countries. LIMITATION:The age-adjusted rates assume that, conditional on age, COVID-19 mortality among diagnosed cases is the same as that among undiagnosed cases and that individuals of all ages are equally susceptible to severe acute respiratory syndrome coronavirus 2 infection. CONCLUSION:Selective testing and identification of older cases considerably warps estimates of the lethality of COVID-19 within populations and comparisons across countries. Removing age distortions and focusing on differences in age-adjusted case fatality will be essential for accurately comparing countries' performance in caring for patients with COVID-19 and for monitoring the epidemic over time. PRIMARY FUNDING SOURCE:Alexander von Humboldt Foundation.
10.7326/M20-2973
Clinical characteristics of 17 patients with COVID-19 and systemic autoimmune diseases: a retrospective study.
Huang Yao,Chen Zhe,Wang Yu,Han Liang,Qin Kai,Huang Wenya,Huang Ying,Wang Hui,Shen Pan,Ba Xin,Lin Weiji,Dong Hui,Zhang Mingmin,Tu Shenghao
Annals of the rheumatic diseases
OBJECTIVES:Increasing data about COVID-19 have been acquired from the general population. We aim to further evaluate the clinical characteristics of COVID-19 in patients with systemic autoimmune diseases (AIDs). METHODS:We included all confirmed inpatients with COVID-19 and systemic AIDs in Wuhan Tongji Hospital from 29 January to 8 March 2020. We retrospectively collected and analysed information on epidemiology of 1255 inpatients and additional clinical characteristics of patients with systemic AIDs. Outcomes were followed up until 16 April 2020. RESULTS:Of the 1255 patients with COVID-19, the median age was 64.0 years and 53.1% were male. More than half (63.0%) had chronic comorbidities. The proportions of elderly, male and patients with comorbidities were significantly higher in intensive care unit (ICU) than in the general ward (p<0.001). 17 (0.61%) patients with systemic AIDs were further screened and analysed from 2804 inpatients. The median age was 64.0 years and 82.4% were female. All patients were living in Wuhan and two family clusters were found. 1 (5.9%) patient was admitted to ICU and one died. 10 (62.5%) of 16 patients changed or stopped their anti-AIDs treatments during hospitalisation, and 5 of them felt that the disease had worsened after the quarantine. CONCLUSIONS:Older males with chronic comorbidities are more vulnerable to severe COVID-19. The lower proportion of COVID-19 in patients with systemic AIDs needs more high-quality human clinical trials and in-depth mechanism researches. Of note, the withdrawal of anti-AIDs treatments during hospitalisation can lead to flares of diseases.
10.1136/annrheumdis-2020-217425